New Triterpenoids for Chemoprevention and Therapy of Cancer

描述（由申请人提供）： 整个项目都是基于这样的假设，即我们可以设计和开发新的合成三萜类化合物，这些化合物最终将在临床上用于癌症的化学预防和治疗。该项目在3个具体目标中阐述，涵盖了临床前研究的整个范围，从新药设计到阐明其生物活性，分子作用机制及其分子靶点;最后，在被认为与实际人类疾病相关的致癌动物模型中测试预防癌症的有效性。我们的具体目标如下：（1）继续合成新的三萜类和三环双烯酮（TBE）用于癌症的化学预防。(2)在一系列与癌症化学预防和化疗相关的细胞培养试验中，继续检测来自特定目标1的新三萜类化合物的生物活性。此类测定测量抗增殖活性、肿瘤细胞分化的诱导、细胞凋亡的诱导和抗炎活性。我们还将使用生物素化的三萜类化合物来鉴定介导三萜类化合物的抗增殖、分化、凋亡和抗炎作用的近似分子靶标。结合这些研究，我们将对下游靶点和途径进行进一步研究，以确定分子作用机制。此外，还将开始对TBE在基因阵列实验中的影响进行新的研究。(3)继续在适当的动物模型中测试有前途的新三萜类化合物或TBE，用于癌症的化学预防，特别强调预防胰腺癌、肺癌和肝细胞癌。还将特别强调测试新的三萜类化合物与已知在动物模型中有效的其他化学预防剂的组合。除了化学预防研究之外，我们还将在化疗模式下进行胰腺癌和肺癌实验，等待动物发展出可检测的癌症，然后确定我们的药物是否有效。以前在该资助支持下合成的三萜类化合物已经在I期临床试验中积极用于治疗白血病，淋巴瘤和实体瘤。从历史上看，许多化学预防剂已进入临床使用的癌症预防，首先被证明是积极的治疗方案，我们打算继续追求这种串扰之间的治疗和预防方法的癌症问题的结果提出的新的研究。公共卫生相关性：肺癌、胰腺癌和肝癌是三种毁灭性的常见恶性肿瘤，目前的治疗方法非常不足。控制这三种疾病的一种完全不同的方法是找到一些安全有效的方法来预防它们的发生。该拨款申请涉及预防肺癌，胰腺癌和肝癌的新药的开发和测试，最终目标是使用这些药物来预防高危男性和女性的疾病。

DESCRIPTION (provided by applicant): This entire project is based on the hypothesis that we can design and develop new synthetic triterpenoids that would eventually be clinically useful for chemoprevention and treatment of cancer. The project is articulated in 3 Specific Aims that cover the entire range of preclinical studies, all the way from design of new drugs; to elucidation of their biological activity, their molecular mechanisms of action, and their molecular targets; and finally, testing of efficacy for prevention of cancer in animal models of carcinogenesis that are considered relevant to actual human disease. Our Specific Aims are as follows: (1) To continue to synthesize new triterpenoids and tricyclic bis-enones (TBEs) for chemoprevention of cancer. (2) To continue to test new triterpenoids from Specific Aim 1 for biological activity in a series of cell culture assays relevant to chemoprevention and chemotherapy of cancer. Such assays measure anti-proliferative activity, induction of differentiation in tumor cells, induction of apoptosis, and anti-inflammatory activity. We will also use biotinylated triterpenoids to identify proximate molecular targets mediating the anti-proliferative, differentiating, apoptotic, and anti-inflammatory actions of triterpenoids. In conjunction with these studies, we will conduct further investigations of downstream targets and pathways, to define molecular mechanisms of action. Furthermore, new studies on effects of TBEs in gene array experiments will be started. (3) To continue to test promising new triterpenoids or TBEs in appropriate animal models for chemoprevention of cancer, with special emphasis on prevention of pancreatic, lung, and hepatocellular cancer. Particular emphasis will also be placed on testing of new triterpenoids in combination with other chemopreventive agents that are known to be effective in the animal models. In addition to the chemoprevention studies, we will do pancreatic and lung cancer experiments in a chemotherapy mode, by waiting until the animals have developed detectable cancers and then determining if our agents are effective as treatments. Triterpenoids previously synthesized with support from this grant are already in active use in Phase I clinical trials for treatment of leukemia, lymphoma, and solid tumors. Historically, many chemopreventive agents have entered clinical use for cancer prevention by first being shown to be active in treatment protocols, and we intend to continue to pursue this cross-talk between therapeutic and preventive approaches to the cancer problem with the results of the proposed new studies. PUBLIC HEALTH RELEVANCE: Relevance Lung cancer, pancreatic cancer, and liver cancer are three devastating and common forms of malignancy for which current therapies are extremely inadequate. A totally different approach to control of these three diseases would be to find some safe and effective way to prevent their occurrence. This grant application deals with the development and testing of new drugs to prevent lung, pancreatic, and liver cancer, with the eventual goal of using such drugs to prevent disease in men and women at high risk.